Mitochondrial gene expression and increased oxidative metabolism

Role in increased lifespan of fat-specific insulin receptor knock-out mice

Masa Katic, Adam R. Kennedy, Igor Leykin, Andrew Norris, Aileen Mcgettrick, Stephane Gesta, Stephen J Russell, Matthias Bluher, Eleftheria Maratos-Flier, C. Ronald Kahn

Research output: Contribution to journalArticle

100 Citations (Scopus)

Abstract

Caloric restriction, leanness and decreased activity of insulin/ insulin-like growth factor 1 (IGF-1) receptor signaling are associated with increased longevity in a wide range of organisms from Caenorhabditis elegans to humans. Fat-specific insulin receptor knock-out (FIRKO) mice represent an interesting dichotomy, with leanness and increased lifespan, despite normal or increased food intake. To determine the mechanisms by which a lack of insulin signaling in adipose tissue might exert this effect, we performed physiological and gene expression studies in FIRKO and control mice as they aged. At the whole body level, FIRKO mice demonstrated an increase in basal metabolic rate and respiratory exchange ratio. Analysis of gene expression in white adipose tissue (WAT) of FIRKO mice from 6 to 36 months of age revealed persistently high expression of the nuclear-encoded mitochondrial genes involved in glycolysis, tricarboxylic acid cycle, β-oxidation and oxidative phosphorylation as compared to expression of the same genes in WAT from controls that showed a tendency to decline in expression with age. These changes in gene expression were correlated with increased cytochrome c and cytochrome c oxidase subunit IV at the protein level, increased citrate synthase activity, increased expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) and PGC-1β, and an increase in mitochondrial DNA in WAT of FIRKO mice. Together, these data suggest that maintenance of mitochondrial activity and metabolic rates in adipose tissue may be important contributors to the increased lifespan of the FIRKO mouse.

Original languageEnglish (US)
Pages (from-to)827-839
Number of pages13
JournalAging Cell
Volume6
Issue number6
DOIs
StatePublished - Dec 2007
Externally publishedYes

Fingerprint

Mitochondrial Genes
Insulin Receptor
Knockout Mice
Fats
Gene Expression
White Adipose Tissue
Thinness
Adipose Tissue
Insulin
Somatomedin Receptors
Basal Metabolism
Citrate (si)-Synthase
Caloric Restriction
Peroxisome Proliferator-Activated Receptors
Citric Acid Cycle
Oxidative Phosphorylation
Caenorhabditis elegans
Glycolysis
Electron Transport Complex IV
Cytochromes c

Keywords

  • Calorie restriction
  • Diabetes
  • Insulin resistance
  • Mitochondria
  • Obesity
  • PGC-1α

ASJC Scopus subject areas

  • Cell Biology

Cite this

Mitochondrial gene expression and increased oxidative metabolism : Role in increased lifespan of fat-specific insulin receptor knock-out mice. / Katic, Masa; Kennedy, Adam R.; Leykin, Igor; Norris, Andrew; Mcgettrick, Aileen; Gesta, Stephane; Russell, Stephen J; Bluher, Matthias; Maratos-Flier, Eleftheria; Kahn, C. Ronald.

In: Aging Cell, Vol. 6, No. 6, 12.2007, p. 827-839.

Research output: Contribution to journalArticle

Katic, M, Kennedy, AR, Leykin, I, Norris, A, Mcgettrick, A, Gesta, S, Russell, SJ, Bluher, M, Maratos-Flier, E & Kahn, CR 2007, 'Mitochondrial gene expression and increased oxidative metabolism: Role in increased lifespan of fat-specific insulin receptor knock-out mice', Aging Cell, vol. 6, no. 6, pp. 827-839. https://doi.org/10.1111/j.1474-9726.2007.00346.x
Katic, Masa ; Kennedy, Adam R. ; Leykin, Igor ; Norris, Andrew ; Mcgettrick, Aileen ; Gesta, Stephane ; Russell, Stephen J ; Bluher, Matthias ; Maratos-Flier, Eleftheria ; Kahn, C. Ronald. / Mitochondrial gene expression and increased oxidative metabolism : Role in increased lifespan of fat-specific insulin receptor knock-out mice. In: Aging Cell. 2007 ; Vol. 6, No. 6. pp. 827-839.
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